1. Field of the Invention
This invention relates to a method for inducing arterial restenosis in an animal model in order to study potential therapies for application to restenosis occurring in human patients after balloon angioplasty or other coronary interventional procedures.
2. Description of the Prior Art
Blood vessels narrowed or occluded by disease have been surgically repaired or replaced in bypass procedures for many years. More recently, percutaneous transluminal coronary angioplasty (PTCA) and intraluminal endovascular grafting procedures employing PCTA balloons and expandable stents have been developed and widely employed to avoid the expense and trauma of vascular surgery.
Despite the high initial success rate and widespread use of percutaneous transluminal coronary angioplasty (PTCA), restenosis appreciably limits the effectiveness of this valuable revascularization method. (See K. M. Kent, "Restenosis After Percutaneous Transluminal Coronary Angioplasty," Am. J. Cardiol. 61:67G-70G, 1988, and A. J. R. Black, et al, "Repeat Coronary Angioplasty: Correlates of a Second Restenosis," JACC 11:714-718, 1988.) Restenosis occurs in 25-45% of all patients within 6 months, and attempts to pharmacologically prevent or reduce it using anti-platelet agents, anticoagulants, corticosteroids, and calcium channel blockers have been unsuccessful. Mixed results have been reported with oral fish oil therapy and aggressive lipid reduction. See references cited in "Restenosis After Balloon Angioplasty - A Practical Proliferative Model in Porcine Coronary Arteries," by Robert S. Schwartz, et al, Circulation 82(6):2190-2200, December 1990, and "Restenosis and the Proportional Neointimal Response to Coronary Artery Injury: Results in a Porcine Model" by Robert S. Schwartz et al, J Am Coll Cardiol; 19;267-74 February 1992, incorporated herein by reference.
Restenosis develops as a consequence of the injury to the arterial wall by the dilation of the balloon in the PTCA procedure. In this procedure, the angioplasty balloon is inflated within the stenosed vessel, or body passageway, in order to shear and disrupt the wall components of the stenosed vessel to obtain an enlarged lumen. With respect to arterial atherosclerotic lesions, the relatively incompressible plaque remains unaltered while the more elastic medial and adventitial layers of the body passageway stretch around the plaque. This process produces dissection, or a splitting and tearing, of the body passageway wall layers, wherein the intima, or internal surface of the artery or body passageway, suffers fissuring. This dissection forms a "flap" of underlying tissue which may reduce the blood flow through the lumen, or block the lumen. Typically, the distending intraluminal pressure within the body passageway can hold the disrupted layer or flap, in place. If the intimal flap created by the balloon dilation procedure is not maintained in place against the expanded intima, the intimal flap can fold down into the lumen and close off the lumen, or may even become detached and enter the body passageway. When the intimal flap closes off the body passageway, often immediate surgery is necessary to correct this problem.
Although the balloon dilation procedure is typically conducted in the catheterization lab of a hospital, because of the foregoing problem, it is always necessary to have a surgeon on call should the intimal flap block the blood vessel or body passageway. Further, because of the possibility of the intimal flap tearing away from the blood vessel and blocking the lumen, balloon dilations cannot be performed upon certain critical body passageways, such as left main coronary artery, which leads into the heart. If an intimal lap formed by a balloon dilation procedure abruptly comes down and closes off a critical body passageway, such as the left main coronary artery, the patient could die before any surgical procedures could be performed.
Additional disadvantages associated with balloon dilation of elastic vascular stenoses is that many fail because of elastic recoil of the stenotic lesion. This usually occurs due to a high fibrocollagenous content in the lesion and is sometimes due to certain mechanical characteristics of the area to be dilated. Thus, although the body passageway may initially be successfully expanded by a balloon dilation procedure, subsequent, early restenosis can occur due to the recoil of the body passageway wall which decreases the size of the previously expanded lumen of the body passageway. For example, stenoses of the renal artery at the ostium are known to be refractory to balloon dilation because the dilating forces are applied to the aortic wall rather than to the renal artery itself. Vascular stenoses caused by neointimal fibrosis, such as those seen in dialysis-access fistulas, have proved to be difficult to dilate, requiring high dilating pressures and larger balloon diameters. Similar difficulties have been observed in angioplasties of graft-artery anastomotic strictures and postendarterectomy recurrent stenoses. Percutaneous angioplasty of Takayasu arteritis and neurofibromatosis arterial stenoses may show poor initial response and recurrence which is believed due to the fibrotic nature of these lesions.
Accordingly, many attempts have been made to develop expandable intraluminal vascular grafts, and methods for expanding the lumen of a body passageway, which prevents recurrence of stenoses in the body passageway, can be utilized for critical body passageways such as the left main coronary artery of a patient's heart, prevents recoil of the body passageway wall, and allows the intraluminal graft to be expanded to a variable size to prevent migration of the graft away from the desired location, and to prevent rupturing and/or erosion of the body passageway by the expanded graft. See, for example, U.S. Pat. Nos. 4,739,762, 4,922,905, and 4,800,882.
Despite the improvement in PTCA and stent technology and procedures, efforts to reduce or eliminate restenosis after PTCA have largely been unsuccessful. In part, these efforts have been hindered by the lack of knowledge of the pathophysiologic mechanisms of human restenosis, and the lack of an accurate animal restenosis model with substantial proliferation. Histologic observation of restenotic tissue from living patients has become readily available with the advent of directional atherectomy. Given this information, there is considerable interest in identification of an animal model similar to human restenosis.
Previous angioplasty animal models have not addressed the proliferative aspects of restenosis directly, instead concentrating on the atheromatous nature of the lesions. The model described by Sanborn has been frequently utilized. (See T. A. Sanborn, et al, "The Mechanism if Transluminal Angioplasty: Evidence for Formation of Aneurysms in Experimental Atherosclerosis," Circulation 1983; 78: 654-660.) In this model rabbits fed atherogenic diets have serum cholesterol levels frequently exceeding 1000 mg %. The resulting atheromatous lesions of the aorta, iliac and femoral vessels contain many foam cells in addition to intimal thickening. Although balloon denudation of endothelium increases proliferation, many foam cells are present in contrast to human restenosis. Another model of restenosis in pig carotid arteries involves endothelial denudation with neointimal proliferation. In this model, however, significant proliferative stenosis are not produced unless caused by occluding, organized thrombus. The carotid or iliac arteries of these models contain proportionally more elastin and are elastic vessels, while the coronary arteries contain proportionally more smooth muscle. These non-coronary vessels may thus be less suitable for a coronary artery restenosis model since smooth muscle proliferation is likely a major factor in the genesis of restenosis.
Lack of a practical animal restenosis model has limited the ability to investigate such potential therapies. If such a model were available, it might have the additional benefit of yielding insight into the mechanisms of the restenosis process itself. In "A Practical Proliferative Model in Porcine Coronary Arteries," by Robert S. Schwartz, et al, Circulation 82(6):2190-2200, December 1990 and "Restenosis and the Proportional Neointimal Response to Coronary Artery Injury: Results in a Porcine Model" by Robert S. Schwartz et al, J Am Coll Cardiol; 19;267-74 February 1992, we describe an experimental animal model of human coronary restenosis developed in domestic swine which accurately mimics the proliferative component of human restenosis, and is practical as well as inexpensive.